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WO1998033779A1 - Derive 3-amino-1,2-benzoisoxazole, procede de preparation et utilisation - Google Patents

Derive 3-amino-1,2-benzoisoxazole, procede de preparation et utilisation Download PDF

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Publication number
WO1998033779A1
WO1998033779A1 PCT/KR1998/000023 KR9800023W WO9833779A1 WO 1998033779 A1 WO1998033779 A1 WO 1998033779A1 KR 9800023 W KR9800023 W KR 9800023W WO 9833779 A1 WO9833779 A1 WO 9833779A1
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WO
WIPO (PCT)
Prior art keywords
amino
ltb
formula
compound
derivatives
Prior art date
Application number
PCT/KR1998/000023
Other languages
English (en)
Inventor
Hong-Suk Suh
Jae-Ha Ryu
Yong-Nam Han
Sung-June Yoon
Jong-Woo Kim
Original Assignee
Dong Wha Pharm. Ind. Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dong Wha Pharm. Ind. Co., Ltd. filed Critical Dong Wha Pharm. Ind. Co., Ltd.
Priority to EP98902278A priority Critical patent/EP1019384A1/fr
Priority to CA002278190A priority patent/CA2278190A1/fr
Priority to US09/355,195 priority patent/US6150390A/en
Priority to JP53274098A priority patent/JP3191943B2/ja
Publication of WO1998033779A1 publication Critical patent/WO1998033779A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a novel 3-amino-l, 2- benzoisoxazole derivatives, represented by Formula I, LTB-4 [leukotriene-B-4 ; 5 ( S) , 12 (R) -dihydroxy- 6, 14-cis-8 , 10- tra ⁇ s-eicosatetraenoic acid] receptor antagonist, process for preparation thereof, and use thereof for LTB-4 receptor antagonist or therapeutics for osteoporosis .
  • Formula I LTB-4 [leukotriene-B-4 ; 5 ( S) , 12 (R) -dihydroxy- 6, 14-cis-8 , 10- tra ⁇ s-eicosatetraenoic acid] receptor antagonist
  • n integer of 3-5
  • LTB-4 natural product, is metabolite of arachidonate , produced in the path way of 5-lipoxygenase
  • LTB-4 induces cohesion and degranulation of neutrophil, and promotes chemical taxis and locomotion of leukocyte, and LTB-4 contracts smooth muscle, and participate in the production of peroxide, and is also detected in a large amount at inflammatory lesions of patient, such as psoriasis, enteritis, rheumatoid arthritis, bronchial asthma, and adult respiratory distress syndrome.
  • Usual LTB-4 receptor antagonists were SM-9064 (Namiki, M. et al . , Biochem. Siophys . Res . Comm . 138 , 540-546, 1986); U-75302 (Morris , J. et al . , Tetrahedron Lett . 29 , 143-146, 1988); LY-255283 (Herron, D.K. et al . , FASEB J. 2, A1110, 1988); SC-41930 (Djuric , S. . et al., J " . Med. Chem. 32, 1145-1147, 1989); LY-223982 (Gapinski, D. , M. et al .
  • Bone reporption and remodeling is continuously recycled, to carry out the above functions, and is in the dynamic state of metabolite with resorbing and remodeling of bone.
  • the remodeling of bone does not equilibrate the resorption of bone, the resorption is relatively superior to the remodeling of bone, and it causes the reduction of bone density and mass to osteoporosis, which is in the state of not maintaining of bony strength. Osteoporosis is very frequently occurred in middle aged and old women.
  • osteoporosis so far, have been developed to inhibit the resorption of bone by inhibiting the action of osteoclast cells. Fracturability by the reduction of bone mass may be not recovered only by inhibiting the resorption of bone. For the ideal treatment of osteoporosis, the recovery from the fracturability, there is necessity that the medicine inhibit the resorption of bone and accelerate the remodeling of bone.
  • inventors have synthesized various compounds and examined their effect of antagonizing LTB-4 receptor and of accelerating the bone formation in order to inhibit and treat the disease relevant to LTB-4 and osteoporosis.
  • the present inventors completed the invention through synthesizing 3-amino-l,2- benzoisoxazole derivatives, represented by Formula I, and identifying their effect of antagonizing LTB-4 receptor and of accelerating the bone formation.
  • the present invention has an object to provide novel 3 -amino-1 , 2 -benzoisoxazole derivatives, represented by Formula I .
  • the present invention has another object to provide process for preparation of 3 -amino-1 , 2 -benzoisoxazole derivatives, represented by Formula I.
  • the present invention has another object to provide pharmaceutical composition containing one of 3-amino-l,2- benzoisoxazole derivatives, represented by Formula I, in effective amount which can antagonize LTB-4 receptor.
  • the present invention has another object to pharmaceutical composition containing one of 3-amino-l,2- benzoisoxazole derivatives, represented by Formula I, in effective amount which can accelerate the bone formation.
  • compounds of Formula II to IV according to the present invention can be utilized as inhibitor and therapeutics for the disease relevant to LTB-4 or osteoporosis, because the compounds have effects of LTB-4 receptor antagonist and of accelerating the bone formation.
  • Compounds according to the present invention can be administered in effective amount to inhibit the action of LTB-4 receptor or to treat osteoporosis by various administrable path; and the form and dose thereof can be determined by those skilled in the art in consideration of administrative object; administrable path; and status and weight of patient.
  • LTB-4 receptor antagonist or therapeutics for osteoporosis preferably contains both one of 3-amino- 1, 2 -benzoisoxazole derivatives, represented by Formula I, and pharmaceutically acceptable carriers.
  • These carriers can be selected from the group comprising the standard pharmaceutically acceptable carriers, which is commonly used in, pasteurized solution, tablet, coated tablet , and capsule.
  • These carriers typically, contain bulking agent, such as starch, milk, sugar, specific clay, gelatin, stearic acid, talc, vegetable fat or oil, gum and glycols, etc. or other kind of known bulking agent.
  • sweetening agent, coloring additives and other component can be contained in the carriers .
  • Composition, which contain these carriers, can be formatted by the known method.
  • LTB-4 receptor antagonist and therapeutics for osteoporosis can be administered by the known manner, such as oral dose, intravenous, intramuscular, and percutaneous injection, and so on. But it is not limited to these manner.
  • 3-amino-l,2- benzo-isoxazole derivatives may be contained in a very extensive range of amount in the pharmaceutical composition.
  • Effective amount of 3-amino-l, 2-benzo- isoxazole for LTB-4 receptor antagonist or therapeutics for osteoporosis is 10 - 1000 mg/day.
  • Dose of composition and its frequency can be easily determined by those skilled in the art according to characteristics of administrative form; status and weight of patient; size of inflammatory lesions; path and frequency of administration; and characteristics of specific derivatives to be used.
  • Process for preparation of compound according to the present invention comprises steps, represented by Scheme I, with the following 4-hydroxy-3-methoxybenzoic acid(l) as starting material, and the specific condition of reaction is shown in the Examples, as follows: Scheme I
  • IV is 2-fluoro-4-hydroxybenzonitrile; V is acetoneoxime;
  • VI is hydrochloric acid
  • DMSO dimethyl sulfoxide
  • GF/C glass fiber filter type C
  • HBSS media Hank's balanced salt solution
  • N,N-Diisopropyl-4 -hydroxy- 3 -methoxybenzamide obtained in the above Step 1, (2.0 g, 7.96 mmol) was dissolved in DMF(30 ml) , and hereto was added potassium carbonate (1.32 g, 9.55 mmol). The reaction mixture was stirred for 30 minutes, then hereto was added dibromo- butane(1.14 ml, 9.55 mmol), and refluxed for 5 hours. After diluting the reaction mixture with ethyl acetate (20 ml) , it was washed with aqueous solution of hydrochloric acid (IN), aqueous solution of sodium chloride, and distilled water.
  • aqueous solution of hydrochloric acid (IN) aqueous solution of sodium chloride
  • N , N-Dii sopropyl - 4 - (4 -bromobutoxy) -3-methoxy- benzamide, obtained by the above Step 2, (1.9 g, 4.92 mmol) was dissolved in acetone (30 ml), and hereto was added sodium iodide (Nal; 1.87 g, 9.84 mmol) .
  • the reaction mixture was refluxed for 10 hours, and the solvent was removed.
  • the resultant was dissolved in diethyl ether, and the organic layer was washed with aqueous solution of sodium chloride and distilled water. The organic layer was dried over anhydrous magnesium sulfate, and removed the solvent.
  • Step 4 Preparation of N,N-diisopropyl-4- [ (2-fluoro- benzonitrile-4 -yloxy) butoxy] - 3 -methoxybe za ide
  • compound (5a) 2-Fluoro-4-hydroxybenzonitrile (0.403 g, 2.98 mmol) was dissolved in DMF(20 ml) , then hereto was added sodium hydride (0.16 g, 3.58 mmol) at 0°C, and stirred for 20 minutes.
  • Compound (4a) (1.41 g, 3.28 mmol) was dissolved in DMF(10 ml), and it was added to the above mixture.
  • Acetoneoxime (0.52 g, 7.15 mmol) was dissolved in DMF(20 ml), and hereto was added potassium t-butoxide (0.80 g, 7.15 mmol) .
  • the reaction mixture was stirred for 30 minutes, then hereto was added compound (5a) (0.586 g, 1.43 mmol), and stirred for 5 hours.
  • the resultant was poured into the mixed solution of aqueous solution of ammonium chloride and diethyl ether, then the organic layer was separated and washed with distilled water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed.
  • Compound (3b) was prepared by the same condition of Step 2 in the Example 1, except for replacing dibromo- butane with dibromo- propane, and from this compound (6b) was prepared by the same condition of Example 1 through the intermediates, compound (3b) , (4b), and (5b) .
  • Neutrophil was separated from whole blood of human by precipitation using "Dextran T-500", and by the inclined centrifugation with Ficoll/Paque (Pharmacia Co. )
  • Degree of antagonizing action in Table I is represented as inhibitory degree of selective binding which is % value of samples to the control, and IC 50 was meant to concentration of 50% of antagonizing in binding to receptor.
  • IC 50 was meant to concentration of 50% of antagonizing in binding to receptor.
  • fetal bovine serum Approximately 30 of calvariae of fetal rat, removed all the tissue, was dissolved in 5 ml sterilized colagenase (0.1%) and trypsin solution (0.05 %) at 37°C. 20 Minutes after dissolving, the released cells were collected, and hereto was added fetal serum to the same amount. This procedure was carried out for 3-6 times in every 20 minutes to collect the isolated cells. Collected cells were separated by centrifugation (400 Xg) for 5 minutes and it was suspended in ⁇ -MEM media, containing 10% (v/v) fetal bovine serum. Collected cells were cultivated in petri dish for 2-3 days, then separated with trypsin, and it were placed in 96 wells to 2.0xl0 3 cells/100 ⁇ l in each well.
  • the compounds of this invention especially accelerate the remodeling of bone in concentration, which is 10,000 times less than concentration of cell toxicity.
  • the compounds of this invention can be therapeutics for osteoporosis as a stimulant of bone formation.
  • the compound, represented by Formula I antagonize LTB-4 receptor and stimulate the bone formation effectively. Therefore, it is expected that good inhibitory and treating effect for the numerous disease relevant to LTB-4 or osteoporosis can be obtained through containing the compound of this invention.
  • the compounds of this invention can especially stimulate the formation of bonelike nodule, so it can be usefully utilized as therapeutics for osteoporosis.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un dérivé 3-amino-1,2-benzoisoxazole représenté par la formule générale (I) dans laquelle n est un entier valant de 3 à 5, lequel dérivé est un antagoniste du récepteur du LTB-4 [leukotriène-B-4; acide 5(S),12(R)-dihydroxy-6,16-cis-8,10-trans-éocisatétraénoïque]. L'invention concerne également des procédés de préparation de tels dérivés et l'utilisation de tels dérivés comme antagonistes du récepteur du LTB-4 ou comme agent thérapeutique contre l'ostéoporose.
PCT/KR1998/000023 1997-02-04 1998-02-04 Derive 3-amino-1,2-benzoisoxazole, procede de preparation et utilisation WO1998033779A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98902278A EP1019384A1 (fr) 1997-02-04 1998-02-04 Derive 3-amino-1,2-benzoisoxazole, procede de preparation et utilisation
CA002278190A CA2278190A1 (fr) 1997-02-04 1998-02-04 Derive 3-amino-1,2-benzoisoxazole, procede de preparation et utilisation
US09/355,195 US6150390A (en) 1997-02-04 1998-02-04 3-amino-1,2-benzoisoxazole derivatives, process for preparation, and use thereof
JP53274098A JP3191943B2 (ja) 1997-02-04 1998-02-04 ３−アミノ−１，２−ベンゾイソオキサゾール誘導体類とその製造方法及び用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1997/3356 1997-02-04
KR19970003356 1997-02-04

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WO1998033779A1 true WO1998033779A1 (fr) 1998-08-06

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US (1) US6150390A (fr)
EP (1) EP1019384A1 (fr)
JP (1) JP3191943B2 (fr)
KR (1) KR100513302B1 (fr)
CN (1) CN1244196A (fr)
CA (1) CA2278190A1 (fr)
WO (1) WO1998033779A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003040113A1 (fr) * 2001-11-06 2003-05-15 Dong Wha Pharm. Ind. Co., Ltd. Derives de 3-amido-1,2-benzoisoxazole et leur procede de preparation et d'utilisation
WO2005102990A1 (fr) * 2004-04-22 2005-11-03 Warner-Lambert Company Llc Modulateurs des androgenes
WO2006004370A1 (fr) * 2004-07-05 2006-01-12 Dong Wha Pharmaceutical. Ind. Co., Ltd. Composition pour la prevention et le traitement de maladies inflammatoires allergiques
WO2006004369A1 (fr) * 2004-07-05 2006-01-12 Dong Wha Pharmaceutical. Ind. Co., Ltd. Composition pharmaceutique servant a traiter des fractures osseuses
US7507860B2 (en) 2004-04-13 2009-03-24 Pfizer Inc. Androgen modulators
US7576128B2 (en) 2004-02-13 2009-08-18 Pfizer Inc. Androgen receptor modulators
US7670613B2 (en) 2004-07-08 2010-03-02 Pfizer Inc. Androgen modulators
US7674819B2 (en) 2005-05-05 2010-03-09 Warner-Lambert Company Llc Androgen modulators

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KR100454767B1 (ko) * 2001-07-19 2004-11-03 동화약품공업주식회사 4-[(4-티아졸릴)페녹시]알콕시-벤즈아미딘 유도체의골다공증 예방 및 치료제로서의 용도
KR100705173B1 (ko) * 2001-07-19 2007-04-06 동화약품공업주식회사 엔,엔-디이소프로필-4-[7-(4-아미노페녹시)헵톡시]-3-메톡시벤즈아미드의 골다공증 예방 및 치료제로서의 용도
US8242152B2 (en) 2001-07-19 2012-08-14 Dong Wha Pharmaceutical Co., Ltd. Use of 4-[(4-thiazolyl)phenoxy]alkoxy-benzamidine derivatives for the prophylaxis and treatment of osteoporosis
WO2006004368A1 (fr) * 2004-07-05 2006-01-12 Dong Wha Pharmaceutical. Ind. Co., Ltd. Methode amelioree servant a preparer n-hydroxy-4{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenoxy]-pentoxy}-benzamidine
KR20060017929A (ko) * 2004-08-04 2006-02-28 동화약품공업주식회사 티아졸 유도체가 치환된 신규한 벤즈아미딘 유도체, 그의제조방법 및 이를 유효성분으로 하는 약학 조성물
EP1947942B1 (fr) * 2005-08-18 2015-07-29 Accelalox, Inc. Methodes de traitement osseux par modulation d'une voie metabolique ou de signalisation de l'acide arachidonique
WO2009105723A2 (fr) * 2008-02-22 2009-08-27 Accelalox, Inc. Nouveaux procédés de traitement d'un os par modulation d'une voie métabolique ou par signalisation de l'acide arachidonique
WO2010013969A2 (fr) * 2008-08-01 2010-02-04 Dong Wha Pharmaceutical Co., Ltd. Composition pharmaceutique pour prévenir ou traiter l'ostéoporose à base de dérivés de benzamidine ou de sels de ceux-ci, et d'acide alendronique ou de sels de celui-ci
KR20100014090A (ko) * 2008-08-01 2010-02-10 동화약품주식회사 벤즈아미딘 유도체 또는 이의 염, 및 비스포스포네이트를 포함하는 골다공증의 예방 또는 치료용 약학 조성물
JP6619773B2 (ja) * 2017-06-12 2019-12-11 武蔵 絵美理 国際標準化機構規格コンテナの天板上に使用する基本部材を使用する太陽光パネル設置台

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EP0048162A1 (fr) * 1980-09-16 1982-03-24 Eli Lilly And Company Isoxazolylbenzamides
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JPS5726662A (en) * 1980-07-24 1982-02-12 Dainippon Pharmaceut Co Ltd Disubstituted-aminoalkoxybenzene derivative
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Title
CHEMICAL ABSTRACTS, Vol. 126, No. 19, 12 May 1997, (Columbus, Ohio, USA), page 554, Abstract No. 251094y, SUH H. et al., "3-Amino-1,2-Benzisoxazoles: A New Family of Potent Inhibitors of LTB4 Binding to the Human Neutrophils"; & BIOORG. MED. CHEM. LETT., 1997, 7(4), 389-392 (Eng). *
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003040113A1 (fr) * 2001-11-06 2003-05-15 Dong Wha Pharm. Ind. Co., Ltd. Derives de 3-amido-1,2-benzoisoxazole et leur procede de preparation et d'utilisation
US7291638B2 (en) 2001-11-06 2007-11-06 Dongwha Pharm. Ind. Co., Ltd. 3-amido-1,2-benzoisoxazole derivatives, process for preparation, and use thereof
KR100789567B1 (ko) * 2001-11-06 2007-12-28 동화약품공업주식회사 3-아미도-1,2-벤조이소옥사졸 유도체, 그 염, 제조방법 및 용도
US7576128B2 (en) 2004-02-13 2009-08-18 Pfizer Inc. Androgen receptor modulators
US7507860B2 (en) 2004-04-13 2009-03-24 Pfizer Inc. Androgen modulators
WO2005102990A1 (fr) * 2004-04-22 2005-11-03 Warner-Lambert Company Llc Modulateurs des androgenes
US7473711B2 (en) 2004-04-22 2009-01-06 Pfizer Inc. Androgen modulators
WO2006004369A1 (fr) * 2004-07-05 2006-01-12 Dong Wha Pharmaceutical. Ind. Co., Ltd. Composition pharmaceutique servant a traiter des fractures osseuses
WO2006004370A1 (fr) * 2004-07-05 2006-01-12 Dong Wha Pharmaceutical. Ind. Co., Ltd. Composition pour la prevention et le traitement de maladies inflammatoires allergiques
CN101022800B (zh) * 2004-07-05 2010-05-05 同和药品株式会社 用于治疗骨折的药物组合物
CN1997367B (zh) * 2004-07-05 2010-11-24 同和药品株式会社 预防和治疗过敏性炎症的组合物
US7923443B2 (en) 2004-07-05 2011-04-12 Dong Wha Pharmaceutical Co., Ltd. Pharmaceutical composition for the treatment of bone fracture
US7670613B2 (en) 2004-07-08 2010-03-02 Pfizer Inc. Androgen modulators
US7674819B2 (en) 2005-05-05 2010-03-09 Warner-Lambert Company Llc Androgen modulators

Also Published As

Publication number Publication date
US6150390A (en) 2000-11-21
KR19980071076A (ko) 1998-10-26
KR100513302B1 (ko) 2005-11-11
JP3191943B2 (ja) 2001-07-23
CN1244196A (zh) 2000-02-09
CA2278190A1 (fr) 1998-08-06
JP2000507971A (ja) 2000-06-27
EP1019384A1 (fr) 2000-07-19

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